Method and apparatus for rapid and safe pulmonary vein cardiac ablation

ABSTRACT

An apparatus includes a shaft, the shaft including a plurality of stepped sections along the length of the shaft. The apparatus further includes a plurality of electrodes disposed along the length of the shaft, each electrode characterized by a geometric aspect ratio of the length of the electrode to the outer diameter of the electrode. Each electrode is located at a different stepped section of the plurality of stepped sections of the shaft and includes a set of leads. Each lead of the set of leads is configured to attain an electrical voltage potential of at least about 1 kV. The geometric aspect ratio of at least one electrode of the plurality of electrodes is in the range between about 3 and about 20.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of and priority to U.S. ProvisionalApplication Ser. No. 62/122,152, entitled “METHOD AND APPARATUS FORRAPID AND SAFE PULMONARY VEIN CARDIAC ABLATION” and filed Oct. 14, 2014,the disclosure of which is incorporated herein by reference in itsentirety.

BACKGROUND

The embodiments described herein relate generally to medical devices fortherapeutic electrical energy delivery, and particularly to systems andmethods of high voltage electrical energy delivery in the context ofablating tissue rapidly and selectively by the application of pulsedvoltage waveforms to produce exogenous electric fields to causeirreversible electroporation of tissue with the aid of suitablypositioned catheter devices with multiple electrodes.

In the past two decades, the technique of electroporation has advancedfrom the laboratory to clinical applications, while the effects of briefpulses of high voltages and large electric fields on tissue has beeninvestigated for the past forty years or more. Application of brief,high DC voltages to tissue, thereby generating locally high electricfields typically in the range of hundreds of Volts/centimeter, candisrupt cell membranes by generating pores in the cell membrane. Whilethe precise mechanism of this electrically-driven pore generation (orelectroporation) is not well understood, it is thought that theapplication of relatively large electric fields generates instabilitiesin the lipid bilayers in cell membranes, causing the occurrence of adistribution of local gaps or pores in the membrane. If the appliedelectric field at the membrane is larger than a threshold value, theelectroporation is irreversible and the pores remain open, permittingexchange of material across the membrane and leading to necrosis and/orapoptosis (cell death). Subsequently the tissue heals in a naturalprocess.

Some known processes of adipose tissue reduction by freezing, also knownas cryogenically induced lipolysis, can involve a significant length oftherapy time. In contrast, the action of irreversible electroporationcan be much more rapid. Some known tissue ablation methods employingirreversible electroporation, however, involve destroying a significantmass of tissue, and one concern is the temperature increase in thetissue resulting from this ablation process.

While pulsed DC voltages are known to drive electroporation under theright circumstances, known approach do not provide for ease ofnavigation, placement and therapy delivery from one or more devices andfor safe energy delivery, especially in the context of ablation therapyfor cardiac arrhythmias with epicardial catheter devices.

Thus, there is a need for devices that can effectively deliverelectroporation ablation therapy selectively to tissue in regions ofinterest while minimizing damage to healthy tissue. In particular, thereis a need for devices that can efficiently deliver electroporationtherapy to desired tissue regions while at the same time minimizing theoccurrence of irreversible electroporation in undesired tissue regions.Such elective and effective electroporation delivery methods withenhanced safety of energy delivery can broaden the areas of clinicalapplication of electroporation including therapeutic treatment of avariety of cardiac arrhythmias.

SUMMARY

An apparatus includes a shaft, the shaft including a plurality ofstepped sections along the length of the shaft. The apparatus furtherincludes a plurality of electrodes disposed along the length of theshaft, each electrode characterized by a geometric aspect ratio of thelength of the electrode to the outer diameter of the electrode. Eachelectrode is located at a different stepped section of the plurality ofstepped sections of the shaft and includes a set of leads. Each lead ofthe set of leads is configured to attain an electrical voltage potentialof at least about 1 kV. The geometric aspect ratio of at least oneelectrode of the plurality of electrodes is in the range between about 3and about 20.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a schematic illustration of a catheter with a multiplicity offlexible electrodes disposed along its shaft, with an electrical leadattached to the inner surface of each electrode, and with a magneticmember located near the distal end of the catheter, according toembodiments.

FIG. 2 is an illustration showing two catheters, each with multipleflexible electrodes disposed along its shaft and wrapped around aportion of the pulmonary veins of the heart in a subject body, with thedistal ends of the two catheters in close proximity, according toembodiments. The two catheters together constitute an approximatelyclosed contour around the pulmonary veins and each catheter positionedin the epicardial space around the heart.

FIG. 3 is a schematic of a two dimensional model of a cardiac atrium,with various regions such as a myocardium disposed around an interiorregion of blood pool, a ring of electrodes around the myocardium, andpericardial fluid in an external region.

FIG. 4 is a simulation result in the form of a shaded contour plot ofthe electric potential, with a voltage difference set between twoelectrodes on opposite sides of the myocardium and all other electrodesreplaced by insulation, according to embodiments.

FIG. 5 is a simulation result corresponding to the situation in FIG. 4,in the form of a shaded contour plot of the electric field magnitude inregions where the latter is at least 200 V/cm. with a voltage differenceset between two electrodes on opposite sides of the myocardium and allother electrodes replaced by insulation, according to embodiments.

FIG. 6 is a simulation result in the form of a shaded contour plot ofthe electric potential, with a voltage difference set between oneelectrode on one side of the myocardium and a set of three contiguouselectrodes (separated by insulation between successive pairs) on theopposite side of the myocardium, and all other electrodes replaced byinsulation, according to embodiments.

FIG. 7 is a simulation result corresponding to the situation in FIG. 6,in the form of a shaded contour plot of the electric field magnitude inregions where the latter is at least 200 V/cm, with a voltage differenceset between one electrode on one side of the myocardium and a set ofthree contiguous electrodes (separated by insulation between successivepairs) on the opposite side of the myocardium, and all other electrodesreplaced by insulation, according to embodiments.

FIG. 8 is a simulation result in the form of a shaded contour plot ofthe electric potential, with a voltage difference set between a set offive contiguous electrodes on one side of the myocardium and a set offive contiguous electrodes on the opposite side of the myocardium, andall other electrodes replaced by insulation, according to embodiments.

FIG. 9 is a simulation result corresponding to the situation in FIG. 8,in the form of a shaded contour plot of the electric field magnitude inregions where the latter is at least 200 V/cm, with a voltage differenceset between a set of three contiguous electrodes (separated byinsulation between successive pairs) on one side of the myocardium and aset of three contiguous electrodes (separated by insulation betweensuccessive pairs) on the opposite side of the myocardium, and all otherelectrodes replaced by insulation, according to embodiments.

FIG. 10A is an illustration of a catheter with a multiplicity offlexible electrodes disposed along its shaft, each in the form of a coilwound around a stepped structure of the catheter shaft, where the stepstructure of the shaft and the coil thickness are such that the outersurface of the catheter forms a smooth structure with an even or smoothdiameter profile, according to embodiments.

FIG. 10B is an illustration of construction of two flexible electrodes,according to embodiments.

FIG. 11 is a schematic illustration of an irreversible electroporationsystem that includes a voltage/signal generator, a controller capable ofbeing configured to apply voltages to selected subsets of electrodeswith independent subset selections for anode electrodes on one medicaldevice and cathode electrodes on a second medical device and that isconnected to a computer, and two or more medical devices connected tothe controller, according to embodiments.

FIG. 12 is an illustration of an ECG waveform showing the refractoryperiods during atrial and ventricular pacing during which a time windowfor irreversible electroporation ablation can be chosen, according toembodiments.

FIG. 13 is a schematic illustration of a waveform generated by theirreversible electroporation system according to embodiments, showing abalanced square wave.

FIG. 14 is a schematic illustration of a waveform generated by theirreversible electroporation system according to embodiments, showing abalanced biphasic square wave.

FIG. 15 is a schematic illustration of a waveform generated by theirreversible electroporation system according to embodiments, showing aprogressive balanced biphasic square wave.

FIG. 16 is a schematic illustration of a user interface according toembodiments, showing electrodes on two catheters, and buttons forselection or marking of anode electrode subsets and cathode electrodesubsets.

FIG. 17 is a schematic illustration of a user interface, according toembodiments, for selection of anode and cathode electrode subsets,showing a single selected anode electrode on one catheter device and asingle selected cathode electrode on a second catheter device.

FIG. 18 illustrates a first or primary catheter with a multiplicity offlexible electrodes disposed along its shaft with an electrical leadattached to the inner surface of each electrode, and endowed withmultiple lumens through which secondary catheters or microcatheters arepassed to emerge from a lateral surface of the primary catheter, eachsecondary catheter also having a multiplicity of flexible electrodesdisposed along its shaft, according to embodiments.

FIG. 19 provides a schematic illustration of two primary catheters thattogether encircle a set of four pulmonary veins, with two secondarycatheters emerging from each primary catheter so as to conjunctivelywrap a set of electrodes around each individual pulmonary vein,according to embodiments.

FIG. 20 is an illustration of a catheter with a magnet assembly in itsdistal portion, such that a first effective pole of the magnet assemblyis oriented longitudinally and a second effective pole of the magnetassembly oriented laterally, according to embodiments.

FIG. 21 is a schematic illustration of a two dimensional simulationmodel of a cardiac atrium, with four interior pulmonary vein “bloodpool” regions disposed within a region representing the atrium, eachpulmonary vein having an annular vessel wall region, and one of thepulmonary veins having four flat electrodes surrounding it, according toembodiments.

FIG. 22 is a simulation result in the form of a shaded contour plot ofthe electric potential, with a voltage difference set between twoelectrodes on opposite sides of a pulmonary vein, according toembodiments.

FIG. 23 is a simulation result corresponding to the situation in FIG. 6,in the form of a shaded contour plot of the electric field magnitude,with a voltage difference of 750 V between opposing electrodes around apulmonary vein, according to embodiments.

FIG. 24 is a simulation result corresponding to the situation in FIG. 6,in the form of a shaded contour plot of the electric field magnitude,with a voltage difference of 750 V between two pairs of opposingelectrodes around a pulmonary vein, resulting in the entire peripheralregion of the pulmonary vein being exposed to an electric field strengthmagnitude sufficient to generate irreversible electroporation, accordingto embodiments.

FIG. 25 is a schematic illustration of a user interface according toembodiments, showing electrodes on two primary catheters and electrodeson each of two secondary catheters passed through each primary catheter,and with the interface having buttons for selection or marking of anodeelectrode subsets and cathode electrode subsets.

FIG. 26 is a schematic illustration of a user interface, according toembodiments, for selection of anode and cathode electrode subsets,showing a single selected anode electrode on one primary catheter deviceand a single selected cathode electrode on a secondary catheter devicethat is passed through the primary catheter device.

DETAILED DESCRIPTION

In some embodiments, a system includes a generator unit configured forgenerating pulses, and a controller unit operably coupled to thegenerator unit, the controller unit configured for triggering thegenerator unit to generate one or more pulses. The system also includesa set of pacing leads operably coupled to the controller unit, thecontroller unit, the generator unit, and the set of pacing leadsconfigured for driving the one or more pulses through the pacing leads.The system also includes at least two medical devices including a firstmedical device and a second medical device, each medical device operablycoupled to the controller unit, each medical device including aplurality of electrodes. The controller unit is further configured forselecting one or more first electrodes from the plurality of electrodesof the first medical device and from the plurality of electrodes of thesecond medical device as cathodes for applying the one or more pulses.The controller unit is further configured for selecting one or moresecond electrodes from the plurality of electrodes of the first medicaldevice and from the plurality of electrodes of the second medical deviceas anodes for applying the one or more pulses.

In some embodiments, a device includes a primary catheter, including oneor more electrodes disposed in an intermediate portion of the primarycatheter and one or more electrodes disposed in a distal portion of theprimary catheter. The primary catheter also includes two or morechannels configured for passage of secondary catheters, each channelcontinuous from a proximal portion of the primary catheter to a lateralexit position on the primary catheter, and one or more magnetic membersdisposed in the intermediate portion of the primary catheter. Theprimary catheter also includes and a magnetic member disposed in thedistal portion of the primary catheter. The device further includes atleast two secondary catheters configured for passage through the primarycatheter device, each secondary catheter including one or moreelectrodes in its respective distal portion, and a magnetic member inits respective distal portion. The device also includes, for eachelectrode of the primary catheter and each electrode of the secondarycatheter, an electrical lead attached to the corresponding electrode,each lead configured for, during use, being at an electrical voltagepotential of at least 1 kV without resulting in dielectric breakdown ofthe two or more channels of the primary catheter. A geometric aspectratio of at least one of the electrodes of the primary catheter deviceis in the range between about 3 and about 20.

In some embodiments, a system includes a pulse generator unit configuredto generated voltage pulses, and a controller unit operably coupled tothe pulse generator unit. The controller unit is configured fortriggering the pulses of the generator unit and for applying voltages ofone polarity to a set electrodes of a first medical device and voltagesof an opposite polarity to a set electrodes of a second medical device.The system also includes a set of pacing leads operably coupled to thecontroller unit, the controller unit further configured for drivingpacing signals through the pacing leads. The system also includes aprimary catheter and a secondary catheter operably coupled to thecontroller unit, the primary catheter including a first set ofelectrodes, the secondary catheter including a second set of electrodes.The controller unit is configured for driving voltages through anyelectrode of the first set of electrodes and second set of electrode.The controller unit is further configured for selecting a sequence ofpairs of electrodes from the first set of electrodes and the second setof electrodes. For each pair of electrodes, an electrode of the pair ofelectrodes has an opposite polarity from the other electrode of the pairof electrodes, and an electrode of the pair of electrodes selected fromthe primary catheter, the other electrode of the pair of electrodesselected from the secondary catheter. The controller unit is furtherconfigured for sequential application of voltage pulse trains over thesequence of pairs of electrodes.

In some embodiments, a method includes epicardially inserting twoprimary catheters, each primary catheter including a first set ofelectrodes disposed along its length. The method also includespositioning the primary catheters in conjoined form so as tosubstantially wrap around the pulmonary veins epicardially in a singlecontour. The method also includes passing a secondary catheter througheach primary catheter, each secondary catheter extending out from alateral side of its corresponding primary catheter. Each secondarycatheter includes a second set of electrodes. The method also includes,for each secondary catheter, wrapping the secondary catheter around aportion of a pulmonary vein, and attaching the secondary to anintermediate portion or distal portion of its corresponding primarycatheter, such that the secondary catheter epicardially encircles thepulmonary vein with a series of electrodes selected from the first setof electrodes of its corresponding primary catheter, from the second setof electrodes of the secondary catheter, or both. The method alsoincludes selecting a set of pairs of electrodes from the first set ofelectrodes of the primary catheters and from the second set ofelectrodes of the secondary catheters, each electrode of each pair ofelectrodes having a cathode or an anode assignment. The method alsoincludes recording electrocardiogram (ECG) signals from at least someelectrodes of the first set of electrodes of the primary catheters andthe second set of electrodes of the secondary catheters. The methodfurther includes identifying refractory intervals in at least one ECGsignal and, in at least one subsequent refractory interval, sequentiallyapplying voltage pulse trains to the set of pairs of electrodes.

An apparatus includes a catheter shaft, and a set of flexible electrodesdisposed along the length of the catheter shaft. Each flexible electrodeis characterized by a geometric aspect ratio of the length of theflexible electrode to the outer diameter of the flexible electrode. Eachflexible electrode includes a set of conducting rings separated byspaces and disposed along the catheter shaft. The set of conductingrings of each flexible electrode are electrically connected together soas to electrically define a common electrical potential for the eachelectrode. The catheter shaft includes gaps configured for separatingadjacent flexible electrodes of the set of flexible electrodes. Theapparatus also includes electrical leads attached to each of theflexible electrodes, each electrical lead configured for attaining anelectrical voltage potential of at least 1 kV. The geometric aspectratio of at least one of the flexible electrodes is in the range betweenabout 3 and about 20

The terms “about” and “approximately” when used in connection with areferenced numeric indication means the referenced numeric indicationplus or minus up to 10% of that referenced numeric indication. Forexample, the language “about 50” covers the range of 45 to 55.

As used in this specification, the singular forms “a,” “an” and “the”include plural referents unless the context clearly dictates otherwise.Thus, for example, the term “an electrode” is intended to mean a singleelectrode or a plurality/combination of electrodes.

Any of the catheter devices described herein can be similar to theablation catheters described in PCT Publication No. WO2014/025394,entitled “Catheters, Catheter Systems, and Methods for PuncturingThrough a Tissue Structure,” filed on Mar. 14, 2013 (“the '394 PCTApplication), which is incorporated herein by reference in its entirety.

Aspects disclosed herein are directed to catheters, systems and methodsfor the selective and rapid application of DC voltage to driveirreversible electroporation. Catheter devices with flexible electrodesand methods for using a multiplicity of such devices for rapid andeffective ablation of cardiac tissue are disclosed. In some embodiments,the irreversible electroporation system described herein includes avoltage/signal generator and a controller capable of being configured toapply voltages to a selected multiplicity or a subset of electrodes,with anode and cathode subsets being selected independently on distinctmedical devices. The controller is additionally capable of applyingcontrol inputs whereby selected pairs of anode-cathode subsets ofelectrodes can be sequentially updated based on a pre-determinedsequence.

FIG. 1 is a schematic illustration of a catheter with a multiplicity offlexible electrodes disposed along its shaft, with an electrical leadattached to the inner surface of each electrode, and with a magneticmember located near the distal end of the catheter. The catheter shaft801 has a multiplicity of electrodes disposed along an extensive lengthof catheter at least about 5 cm in extent. For clarity, FIG. 1 shows twoflexible electrodes 801 and 805 in the form of a coil wound around thecatheter shaft; in some embodiments, the number of electrodes can be inthe approximate range from two to six. Each electrode attaches to alead, so that in FIG. 1 electrodes 801 and 805 respectively attach toleads 814 and 813.

Further, the distal tip region of the catheter has a magnetic member809. The magnetic member 809 can be in the form of a magnetizable orferromagnetic material, or it may be a magnetized object, with the polesof the magnetized object being either along a straight line or not. Insome embodiments, at least one of the poles of the magnet represents alocal magnetization direction that is substantially aligned with thelongitudinal axis of the catheter.

In one embodiment the metallic, flexible coiled electrodes couldcomprise biocompatible metals such as titanium, platinum or platinumalloys. The catheter shaft is made of a flexible polymeric material suchas for example Teflon, Nylon or Pebax.

In some embodiments, all the electrodes of a catheter have the samepolarity, in which case the need for high dielectric strength materialseparating the leads is not a significant constraint, and the cathetercan be relatively small in diameter, for instance being in the range ofabout 9 French, about 8 French or even about 6 French. Likewise, ahigher voltage can be applied to the electrodes of the catheter as thereis no risk of dielectric breakdown; in some instances, this couldenhance the efficacy of irreversible electroporation ablation. Theflexible electrode has a length 817 (denoted by L) associated with it,and its diameter 818 corresponds to the catheter diameter (denoted byd). The aspect ratio L/d of each flexible electrode is a geometriccharacteristic associated with the flexible electrode. In someembodiments, the aspect ratio of at least one of the flexible electrodeson the device is at least about 3, and at least in the range betweenabout 3 and about 20, and in the range between about 5 and about 10 insome embodiments.

FIG. 2 shows a pair of Pulmonary Vein isolation (PV isolation) ablationcatheter devices, a first device with proximal end 3 and distal end 15,and a second device with proximal end 4 and distal end 16, each with amultiplicity of flexible electrodes disposed along its length. The firstcatheter device has two flexible electrodes labeled 5 and 8 disposedalong its length, while the second catheter device has two flexibleelectrodes labeled 6 and 7. Each catheter is wrapped in the epicardialspace around a portion of the pulmonary veins 10, 11, 12 and 13 of aheart 7 in a subject or patient anatomy, with the proximal portions 3and 4 of the respective catheters extending out and away to eventuallyemerge from the patient's chest. In some embodiments the distal ends 15and 16 of the two catheters have magnetic members that can aid inalignment of the two catheters. A puncturing apparatus using asubxiphoid pericardial access location and a guidewire-based deliverymethod to accomplish the placement of a multi-electrode catheter aroundthe pulmonary veins was described in PCT Patent ApplicationWO2014025394; the same method can be used to deliver and position thetwo catheters in FIG. 2. After the ends 3 and 4 of the two respectivecatheters extend and emerge out of the patient chest they can be cinchedtogether to effectively hold the catheters in place or in stablepositions relative to each other.

A voltage for electroporation can be applied to subsets of electrodesidentified as anodes and cathodes respectively on the two catheters onapproximately opposite sides of the closed contour defined by the shapesof the catheters around the pulmonary veins. The voltage is applied inbrief pulses sufficient to cause irreversible electroporation and can bein the range of 0.5 kV to 10 kV, in the range from about 0.75 kV toabout 2.5 kV, and all values and subranges in between, so that athreshold electric field value of about 200 Volts/cm is effectivelyachieved in the cardiac tissue to be ablated. In some embodiments, themarked or active electrodes on the two catheters can be automaticallyidentified, or manually identified by suitable marking, on an X-ray orfluoroscopic image obtained at an appropriate angulation that permitsidentification of the geometric distance between anode and cathodeelectrodes, or their respective centroids. In one embodiment, thevoltage generator setting for irreversible electroporation is thenautomatically identified by the electroporation system based on thisdistance measure. In some embodiments, the voltage value is selecteddirectly by a user from a suitable dial, slider, touch screen, or anyother user interface. The voltage pulse results in a current flowingbetween the anode and cathode electrodes on opposite sides of thecontour defined by the conjoint shapes of the two catheters, with saidcurrent flowing through the cardiac wall tissue and through theintervening blood in the cardiac chamber, with the current entering thecardiac tissue from the anode electrodes and returning back through thecathode electrodes. For the configuration shown in FIG. 2, the forwardand return current paths (leads) are respectively inside distinctcatheters, since all active electrodes on a given catheter are of likepolarity. Areas of cardiac wall tissue where the electric field issufficiently large for irreversible electroporation are ablated duringthe voltage pulse application.

A two dimensional model of a cardiac atrium, with various regions suchas a myocardium disposed around an interior region of blood pool, a ringof electrodes around the myocardium representing a catheter shaft, andpericardial fluid in an external region is shown in FIG. 3, with whichsimulation results can be obtained based on realistic values ofelectrical material properties for the various regions. A ring ofelectrodes 23 comprising a series of cells is disposed around amyocardium 24 which itself encircles a blood pool region 25. An externalpericardial fluid region 26 surrounds the ring of electrodes. Forpurposes of simulation, individual electrode cells such as 27 can bedefined or set to be either metal electrodes or insulation (representingcatheter shaft regions that do not have electrodes) in terms ofelectrical properties.

A simulation result in the form of a shaded contour plot of the electricpotential is shown in FIG. 4 for the case where a voltage is appliedbetween a single anode electrode 30 and a single cathode electrode 31 onopposite sides of the blood pool region, with all other electrode cellsdefined to be insulation in terms of electrical properties. In thesimulation, a voltage difference of about 1 kV was used between theanode and cathode electrodes. FIG. 5 shows the electric field intensityas a contour plot where regions with an electric field strength ofmagnitude at least about 200 V/cm (generally needed to causeirreversible electroporation ablation of myocytes) are indicated by thedarker shaded areas. It is apparent that these ablated regions,indicated by region 35 around the anode electrode and region 34 aroundthe cathode electrode, are quite localized near the electrodes acrosswhich a potential difference is applied.

FIG. 6 illustrates a simulation result in the form of a shaded contourplot of the electric potential for the case where a DC voltage isapplied between a single anode electrode 37 and a set of threesuccessive cathode electrodes 38, 39 and 40 on opposite sides of theblood pool region, with all other electrode cells defined to beinsulation in terms of electrical properties (including cells betweenelectrodes 38 and 39 and between 39 and 40). In the simulation, avoltage difference of about 1 kV was used between the anode and (set of)cathode electrodes. FIG. 7 shows the electric field intensity as acontour plot where regions with an electric field strength of magnitudeat least about 200 V/cm (generally needed to cause irreversibleelectroporation ablation) are indicated by the darker shaded areas. Itis apparent that these ablated regions, indicated by region 44 aroundthe anode electrode and region 43 around the set of cathode electrodes,are quite localized near the electrodes across which a potentialdifference is applied. Furthermore, there are gap regions such as 45 inthe myocardium where the electric field intensity is not large enough togenerate electroporation. In practice, this would mean that repeatedapplications of pulsed DC voltage may be needed with repositioning ofthe catheter shaft(s) and electrodes.

In FIG. 8, a simulation result is displayed in the form of a shadedcontour plot of the electric potential, with a voltage difference setbetween a set of five contiguous electrodes on one side of themyocardium and a set of five contiguous electrodes on the opposite sideof the myocardium, representing respective “long electrodes”, and allother electrodes replaced by insulation. In the simulation, a voltagedifference of about 1 kV was used between the anode electrode set andthe cathode electrode set. FIG. 9 shows the electric field intensity asa contour plot where regions with electric field strength of magnitudeat least about 200 V/cm (generally needed to cause irreversibleelectroporation ablation in myocytes) are indicated by the darker shadedareas. It is apparent that these ablated regions, indicated by region 50around the anode electrode and region 51 around the set of cathodeelectrodes, constitute continuous, fully ablated sections of myocardium.Thus, with a set of longer, flexible electrodes as described in thepresent disclosure, a more rapid and effective delivery of ablationtherapy may be obtained as repositioning of the catheter shaft will beminimized. Furthermore, the catheter devices, in some embodiments, withlong, flexible electrodes can result in a lower peak value of theelectric field. This can minimize or eliminate the possibility ofdielectric breakdown or spark generation during high voltage ablation.For instance, while the peak electric field intensity valuescorresponding to the single cathode and three-cathode situations of FIG.5 and FIG. 7 are respectively about 4,458 V/cm and about 3,916 V/cm, thepeak electric field intensity value that occurs for the case of long,flexible electrodes as in FIG. 8 is about 2,456 V/cm, demonstrating anadvantage of the catheter devices of the present disclosure.

FIG. 10A is a schematic illustration of a catheter with a multiplicityof flexible electrodes disposed along its shaft, with the catheter shaft58 having a stepped construction consisting of higher profile regionssuch as 60 and lower profile or “stepped down” regions 59 and 61.Flexible electrodes are present along the stepped down sections 59 and61 in the form of metallic coils 54 and 55 respectively, such that theoverall diameter profile of the catheter shaft is maintained everywherealong its length in a smooth and continuous manner. Thus the thicknessof the flexible electrode coils 54 and 55 is such that the sum of thestepped down diameter and twice the coil thickness is equal to the outerdiameter of the catheter shaft. The metallic, flexible coiled electrodescould comprise biocompatible metals such as titanium, platinum orplatinum alloys. The catheter shaft is made of a flexible polymericmaterial such as for example Teflon, Nylon or Pebax. In someembodiments, all the electrodes of a catheter have the same polarity, inwhich case the need for high dielectric strength material separatingelectrode leads (not shown in FIG. 10A) is not a significant constraint,and the catheter can be relatively small in diameter, for instance beingin the range of about 9 French, about 8 French or even about 6 French.Likewise, a higher DC voltage can be applied to the electrodes of thecatheter as there is no risk of dielectric breakdown; in some instances,this could enhance the efficacy of irreversible electroporationablation. The flexible electrode has a length 817 (denoted by L)associated with it, and its diameter 818 corresponds to the catheterdiameter (denoted by d). The aspect ratio L/d of each flexible electrodeis a geometric characteristic associated with the flexible electrode. Insome embodiments, the aspect ratio of at least one of the flexibleelectrodes on the device is at least 3, and, in some embodiments, atleast in the range from 5 to 10. Although FIG. 10A shows two electrodesfor purposes of illustration, it should be apparent that the number offlexible electrodes on the catheter can be anywhere from one to fifteenor even greater, depending on the clinical application and convenienceof use. In some embodiments, the catheter could have a combination ofelectrodes such that some electrodes are flexible while others arerigid.

In some embodiments, a flexible electrode may also be constructed in theform of a sequence of thin electrically conducting bands or ringsmounted on a flexible catheter shaft, separated by spaces betweenadjacent rings of the sequence and with the sequence of ringselectrically connected together. In this manner, the sequence of ringsforms a single electrode, the entire sequence presenting an isopotentialsurface across which an electrical current can flow to tissue adjacentto the electrode when the electrode is suitably electrically polarized.The electrical connection between the individual rings of the sequencecan be made by several means, such as, for example, attaching a singleelectrical lead to the inner surface of each ring with one or more spotwelds or laser welding, or by crimping each electrode in place over aportion of an exposed electrical lead that runs on the outer surface ofthe catheter shaft, and so on.

The construction of such a flexible electrode is illustrated in theexample in FIG. 10B, where two such electrodes are shown disposed alonga length of flexible catheter shaft. Each electrode in the figureincludes 3 electrically conducting rings (Rings 1, 2, 3) separated byspaces. FIG. 10B shows 3 rings of widths a₁, a₂ and a₃ with rings 1 and2 separated by a space of width b₁ and rings 2 and 3 separated by aspace of width b₂. Since only the flexible catheter shaft is present inthe spaces, even though the individual rings may be rigid (for example,the rings can be metallic), the electrode itself is effectivelyflexible. The adjacent electrodes are separated by a gap. In thismanner, the catheter itself can also bend in very flexible fashion. Thewidth of each ring of a flexible electrode can lie in the range betweenabout 0.5 mm and about 6 mm, or in the range between about 1 mm andabout 4 mm, including all values and sub ranges in between. The spacesbetween adjacent rings can lie in the range between about 1 mm and about4 mm, including all values and sub ranges in between. Further, the gapsor separation between adjacent distinct electrodes can lie in the rangebetween about 2 mm and about 12 mm, including all values and sub rangesin between.

In the example shown in FIG. 10B, the central or second ring of theflexible electrode is wider than the end rings (1 and 3). While thisexample shows a flexible electrode comprising 3 conducting rings, moregeneral constructions with a larger or smaller multiplicity ofconducting rings can be built by one skilled in the art following thedisclosure herein. Likewise, the separations between adjacent rings canbe varied sequentially, as can the width of each individual ring in thesequence. The above example is provided for non-limiting illustrativepurposes only.

For epicardial use as disclosed in the present application, it is usefulto have a catheter with a certain amount of flexibility. Onecharacterization of flexibility can be made in terms of a radius ofcurvature. In some embodiments, the flexible electrodes are constructedand disposed along the catheter shaft such that about a 2 cm radius ofcurvature of the shaft is achieved with a minimal amount of appliedforce or torque. In some embodiments, a bending moment of about 5×10⁻³N-m applied over an approximately 6 cm length of catheter can result ina bend or end-to-end deflection in the catheter of about 180-degrees orlarger.

The rings of each flexible electrode can be of metallic compositionincluding, but not limited to, stainless steel, silver, gold, anysuitable material comprising a significant proportion of platinum suchas platinum-iridium alloy, combinations thereof, and/or the like.

A schematic diagram of the electroporation system, according to someembodiments, is shown in FIG. 11. A voltage/signal generator 73 isdriven by a controller unit 71 that interfaces with a computer device 74by means of a two-way communication link 79. The controller interfacecan act as a multiplexer unit and perform channel selection and routingfunctions for applying voltages to appropriate electrodes that have beenselected by a user or by the computer 74. The controller can apply thevoltages via a multiplicity of leads to a first catheter device 72, aswell as a second catheter device 70. Active electrodes can be selectedon a first catheter device 72 with one polarity, and likewise activeelectrodes can be selected on a second catheter device 70 with theopposite polarity.

Some leads from the controller 71 could also carry pacing signals todrive pacing of the heart through a separate pacing device (not shown).The catheter devices can also send back information such as ECGrecordings or data from other sensors back to the controller 71,possibly on separate leads. While the voltage generator 73 sends avoltage to the controller 71 through leads 77, the voltage generator isdriven by control and timing inputs 78 from the controller unit 71.

As shown in FIG. 12, given atrial or ventricular pacing inputs to theheart, the resulting ECG waveform 82 has appropriate respectiverefractory time intervals 83 and 84 respectively, during which there aresuitable time windows for application of irreversible electroporation asindicated by 85 and 86. The application of cardiac pacing results in aperiodic, well-controlled sequence of electroporation time windows.Typically, this time window is of the order of hundreds of microsecondsto about a millisecond or more. During this window, multiple voltagepulses can be applied to ensure that sufficient tissue ablation hasoccurred. The user can repeat the delivery of irreversibleelectroporation over several successive cardiac cycles for furtherconfidence.

In one embodiment, the ablation controller and signal generator can bemounted on a rolling trolley, and the user can control the device usinga touchscreen interface that is in the sterile field. The touchscreencan be for example an LCD touchscreen in a plastic housing mountable toa standard medical rail or post and can be used to select the electrodesfor ablation and to ready the device to fire. The interface can forexample be covered with a clear sterile plastic drape. The operator canselect the number of electrodes involved in an automated sequence. Thetouch screen graphically shows the catheters that are attached to thecontroller. In one embodiment the operator can select electrodes fromthe touchscreen with appropriate graphical buttons. The operator canalso select the pacing stimulus protocol (either internally generated orexternally triggered) from the interface. Once pacing is enabled, andthe ablation sequence is selected, the operator can initiate or verifypacing. Once the operator verifies that the heart is being paced, theablation sequence can be initiated by holding down a hand-held triggerbutton that is in the sterile field. The hand-held trigger button can beilluminated red to indicate that the device is “armed” and ready toablate. The trigger button can be compatible for use in a sterile fieldand when attached to the controller can be illuminated a differentcolor, for example white. When the device is firing, the trigger buttonflashes in sequence with the pulse delivery in a specific color such asred. The waveform of each delivered pulse is displayed on thetouchscreen interface. A graphic representation of the pre and postimpedance between electrodes involved in the sequence can also be shownon the interface, and this data can be exported for file storage.

In one embodiment, impedance readings can be generated based on voltageand current recordings across anode-cathode pairs or sets of electrodes(anodes and cathodes respectively being on distinct catheters), and anappropriate set of electrodes that are best suited for ablation deliveryin a given region can be selected based on the impedance map ormeasurements, either manually by a user or automatically by the system.For example, if the impedance of the tissue between an anode/cathodecombination of electrodes is a relatively low value (for example, lessthan 25 Ohms), at a given voltage the said combination would result inrelatively large currents in the tissue and power dissipation in tissue;this electrode combination would then be ruled out for ablation due tosafety considerations, and alternate electrode combinations could besought by the user. In some embodiments, a pre-determined range ofimpedance values, for example 30 Ohms to 300 Ohms, could be used as anallowed impedance range within which it is deemed safe to ablate.

The waveforms for the various electrodes can be displayed and recordedon the case monitor and simultaneously outputted to a standardconnection for any electrophysiology (EP) data acquisition system. Withthe high voltages involved with the device, the outputs to the EP dataacquisition system needs to be protected from voltage and/or currentsurges. The waveforms acquired internally can be used to autonomouslycalculate impedances between each electrode pair. The waveformamplitude, period, duty cycle, and delay can all be modified, forexample via a suitable Ethernet connection. Pacing for the heart iscontrolled by the device and outputted to the pacing leads and aprotected pacing circuit output for monitoring by a lab.

In some embodiments, the system (generator and controller) can deliverrectangular-wave pulses with a peak maximum voltage of about 5 kV into aload with an impedance in the range of about 30 Ohm to about 3,000 Ohmfor a maximum duration of about 200 ps, with a maximum duration of about100 μs, in some embodiments. Pulses can be delivered in a multiplexedand synchronized manner to a multi-electrode catheter inside the bodywith a duty cycle of up to 50% (for short bursts). The pulses cangenerally be delivered in bursts, such as for example a sequence ofbetween 2 and 10 pulses interrupted by pauses of between about 1 ms andabout 1,000 ms. The multiplexer controller is capable of running anautomated sequence to deliver the impulses/impulse trains (from thevoltage signal/impulse generator) to the tissue target within the body.The controller system is capable of switching between subsets ofelectrodes located on the single-use catheters. Further, the controllercan measure voltage and current and tabulate impedances of the tissue ineach electrode configuration (for display, planning, and internaldiagnostic analysis). It can also generate two channels of cardiacpacing stimulus output, and is capable of synchronizing impulse deliverywith the internally generated cardiac pacing and/or an external triggersignal. In one embodiment, it can provide sensing output/connection foraccess to bio potentials emanating from each electrode connected to thesystem (with connectivity characteristics being compatible with standardelectrophysiological laboratory data acquisition equipment).

In some embodiments, the controller can automatically “recognize” eachof the two single-use disposable catheters when it is connected to thecontroller output (prompting internal diagnostics and user interfaceconfiguration options). The controller can have at least two uniqueoutput connector ports to accommodate up to at least two catheters atonce. The controller device can function as long as at least tworecognized catheters are attached to it. In some embodiments, thecontroller can have several sequence configurations that provide theoperator with at least some variety of programming options. In oneconfiguration, the controller can switch electrode configurations of abipolar set of electrodes (cathodes and anodes respectively on distinctcatheters) sequentially, for instance in a clockwise manner (forexample, starting at a given step, in the next step of the algorithm,the next cathode electrode on one catheter and the next anode electrodeon the other catheter are automatically selected, timed to thesynchronizing trigger), with the two catheters and their electrodesarranged in a quasi-circumference around the target. Thus in a firstsequence configuration, pulsed voltage delivery occurs as the automatedsequencing of the controller switches “on” and “off” between differentelectrodes surrounding the tissue target. In a second sequenceconfiguration, the impulses are delivered to user-selected electrodesubsets of catheters that are connected to the device. The user can alsoconfigure the controller to deliver up to 2 channels of pacing stimulusto electrodes connected to the device output. The user can control theapplication of voltage with a single handheld switch. A sterile catheteror catheters can be connected to the voltage output of the generator viaa connector cable that can be delivered to the sterile field. In oneembodiment, the user activates the device with a touch screen interface(that can be protected with a single-use sterile transparent disposablecover commonly available in the catheter lab setting). The generator canremain in a standby mode until the user is ready to apply pulses atwhich point the user/assistant can put the generator into a ready modevia the touchscreen interface. Subsequently the user can select thesequence, the active electrodes, and the cardiac pacing parameters.

Once the catheters have been advanced to or around the cardiac target,the user can initiate electrically pacing the heart (using a pacingstimulus generated by the ablation controller or an external sourcesynchronized to the ablation system). The operator verifies that theheart is being paced and uses the hand-held trigger button to apply thesynchronized bursts of high voltage pulses. The system can continuedelivering the burst pulse train with each cardiac cycle as long as theoperator is holding down a suitable “fire” button or switch. During theapplication of the pulses, the generator output is synchronized with theheart rhythm so that short bursts are delivered at a pre-specifiedinterval from the paced stimulus. When the train of pulses is complete,the pacing continues until the operator discontinues pacing.

The controller and generator can output waveforms that can be selectedto generate a sequence of voltage pulses in either monophasic orbiphasic forms and with either constant or progressively changingamplitudes. FIG. 13 shows a rectangular wave pulse train where thepulses 101 have a uniform height or maximum voltage. FIG. 14 shows anexample of a balanced biphasic rectangular pulse train, where eachpositive voltage pulse such as 103 is immediately followed by a negativevoltage pulse such as 104 of equal amplitude and opposite sign. While inthis example the biphasic pulses are balanced with equal amplitudes ofthe positive and negative voltages, in other embodiments an unbalancedbiphasic waveform could also be used as may be convenient for a givenapplication.

Yet another example of a waveform or pulse shape that can be generatedby the system is illustrated in FIG. 15, which shows a progressivebalanced rectangular pulse train, where each distinct biphasic pulse hasbalanced or equal-amplitude positive and negative voltages, but eachpulse such as 107 is larger in amplitude than its immediate predecessor106. Other variations such as a progressive unbalanced rectangular pulsetrain, or indeed a wide variety of other variations of pulse amplitudewith respect to time can be conceived and implemented by those skilledin the art based on the teachings herein.

The time duration of each irreversible electroporation rectangularvoltage pulse could lie in the range from about 1 nanosecond to about 10milliseconds, with the range about 10 microseconds to about 1millisecond in some embodiments, and the range about 50 microseconds toabout 300 microseconds in some embodiments, including all values and subranges in between. The time interval between successive pulses of apulse train could be in the range of about 10 microseconds to about 1millisecond, with the range about 50 microseconds to about 300microseconds in some embodiments. The number of pulses applied in asingle pulse train (with delays between individual pulses lying in theranges just mentioned) can range from 1 to 100, with the range 1 to 10in some embodiments.

As described in the foregoing, a pulse train can be driven by auser-controlled switch or button or, in some embodiments, mounted on ahand-held joystick-like device. In one mode of operation a pulse traincan be generated for every push of such a control button, while inanother mode of operation pulse trains can be generated repeatedlyduring the refractory periods of a set of successive cardiac cycles, foras long as the user-controlled switch or button is engaged by the user.

All of these parameters can be determined by the design of the signalgenerator, and in various embodiments could also be determined by usercontrol as may be convenient for a given clinical application. Thespecific examples and descriptions herein are exemplary in nature andvariations can be developed by those skilled in the art based on thematerial taught herein.

FIG. 16 shows a portion of a user interface of the electroporationsystem for selection (with graphical buttons 117 and 118) of anode andcathode electrodes, with two catheters connected to the system. Theproximal leads of the two catheters are schematically indicated by 110and 111, which each have two flexible electrodes, respectively 112, 115and 113, 114. The buttons 117 and 118 can enable the selection ofappropriate electrodes on the catheters as respectively anode or cathodewith a “Continue” button 706. Once the selection is made, theappropriate electrodes are colored differently to indicate anode orcathode electrodes as shown marked respectively as anode electrode 115and cathode electrode 113 on the two catheters in FIG. 17.

FIG. 18 shows another embodiment of device of the present disclosure,where a first or primary catheter with a multiplicity of flexibleelectrodes disposed along its shaft (with an electrical lead attached tothe inner surface of each electrode) includes multiple lumens throughwhich secondary catheters or microcatheters can be passed to emerge froma lateral surface of the primary catheter, each secondary catheter alsohaving a multiplicity of flexible electrodes disposed along its shaft.In the illustration, the primary catheter device 131 has flexibleelectrodes 133, 135, 137 and 139 disposed along the length of its shaft,and the device 131 has lumens 142 and 143 through which secondarycatheter devices 145 and 146 are passed. The secondary catheters passthrough the lumens and emerge from a lateral portion of the primarycatheter, in some embodiments on approximately opposite lateral sides ofthe primary catheter 131. The secondary catheters 145 and 146 themselveshave a multiplicity of flexible electrodes disposed along their lengths,shown in FIG. 18 as electrodes 150 and 151 on secondary catheter 145 andas electrodes 153 and 154 on secondary catheter 146, respectively.Electrical leads 180 connect to the electrodes 133, 135, 137 and 139 ofthe primary catheter for delivery of high voltage pulsed signals. In oneembodiment the same leads 180 can also serve to record ECG signals.Likewise electrical leads 171 and 173 connect to electrodes 150 and 151on secondary catheter 145, while electrical leads 175 and 177 connect toelectrodes 153 and 154 on secondary catheter 146. The distal region ofthe primary catheter 131 comprises a magnetic member 164, and magneticmembers such as 166 or 167 are also present within the primarycatheter's shaft at an approximately mid-length position. The distalregions of the secondary catheters 145 and 146 also comprise magneticmembers 160 and 162 respectively. In some embodiments, the magneticmember 164 comprises at least one permanent magnet, while the magneticmembers 160 and 162 comprise magnetizable material such as aferromagnetic material, while the magnetic members 166 and 167 can beeither permanent magnets or electromagnets activated by an electricalcurrent, with their magnetic poles oriented laterally with respect tothe catheter shaft. Further the primary catheter can have a throughlumen (not shown in FIG. 18) for introducing the catheter over aguidewire.

In use, as FIG. 19 illustrates, two primary catheters are introducedepicardially via a subxiphoid approach as described for example in PCTPatent Application No. WO2014025394, where a puncturing apparatus usinga subxiphoid pericardial access location and a guidewire-based deliverymethod to accomplish the placement of a multi-electrode catheter aroundthe pulmonary veins was described in detail. The two primary cathetersjointly encircle a set of four pulmonary veins, with two secondarycatheters emerging from each primary catheter so as to conjunctivelywrap a set of electrodes around each individual pulmonary vein. Fourpulmonary veins marked A, B, C and D are shown in FIG. 19. Primarycatheter 206 wraps around one side (representing an outer contour) ofpulmonary veins marked A and C in FIG. 19, while primary catheter 207wraps around one side (representing an outer contour) of pulmonary veinsmarked B and D in FIG. 19. Secondary catheter 208 branches out from aproximal portion of primary catheter 206, wraps around the inner side ofpulmonary vein A and magnetically attaches to the mid-portion of primarycatheter 206, with a distal magnetic member 231 on secondary catheter208 attaching to a mid-portion magnetic member 230 on primary catheter206. Thus secondary catheter electrodes 215 and 216 and primary catheterelectrodes 220 and 221 collectively are wrapped in a closed contouraround pulmonary vein A. Secondary catheter 229 branches out from amiddle portion of primary catheter 206, wraps around the inner side ofpulmonary vein C and magnetically attaches to the distal portion ofprimary catheter 206, with a distal magnetic member 241 on secondarycatheter 229 attaching to a distal magnetic member 242 on primarycatheter 206. Thus secondary catheter electrodes 213 and 214 and primarycatheter electrodes 210 and 211 collectively are wrapped in a closedcontour around pulmonary vein C. The distal portion of primary catheter206 also magnetically attaches to the distal portion of primary catheter207. Secondary catheters 224 and 225 branch out from primary catheter207 and wrap around pulmonary veins B and D, with a distal magneticmember 234 on secondary catheter 224 attaching to a mid-portion magneticmember 235 on primary catheter 207 and a distal magnetic member 238 onsecondary catheter 225 attaching to a distal magnetic member 239 onprimary catheter 207, respectively. In this manner, each pulmonary veinis wrapped by a set of flexible electrodes for effective electroporationvoltage delivery.

An example of a magnetic member configuration for the distal magneticmember 164 of the primary catheter device in FIG. 18 (or 239 or 242 inFIG. 19) is provided in FIG. 20. The latter figure illustrates acatheter with a magnet assembly in its distal portion, such that a firsteffective pole of the magnet assembly is oriented longitudinally and asecond effective pole of the magnet assembly oriented laterally. Asshown, the catheter 303 comprises an assembly of magnetized material inits distal portion comprising magnetic elements 305, 306 and 307 withrespective magnetization orientations indicated by arrows 308, 309 and310. The assembly comprising the magnetic elements 305, 306 and 307effectively forms a magnetic member with a longitudinally orientedmagnetic pole (denoted by arrow 308) and a laterally oriented magneticpole (denoted by arrow 310). If a second primary catheter has a similarassembly of magnetic elements in its distal portion with an oppositeorientation of its longitudinal and lateral magnetic poles, the distaltips of the two primary catheters can attach magnetically. As mentionedearlier, magnetic members in the mid-portion of the primary catheter canfor example be in the form of electromagnets, providing a means ofattachment of the distal tip of a secondary catheter to the mid-portionof a primary catheter, and this attachment mechanism provides anexemplary means for configuring a set of primary and secondary cathetersas shown in FIG. 19. While the examples and attachment means describedherein provides one method of magnetic attachment, other similar methodscan be conceived and implemented by one skilled in the art by followingthe embodiments disclosed herein.

FIG. 21 shows an illustration of a two dimensional model of a cardiacatrium, with an atrial tissue region 320 that has interior “blood pool”regions 321, 322, 323 and 324. Each blood pool region represents apulmonary vein and is surrounded by a thin annular such as for examplethe ring-shaped region 337 around pulmonary vein 322. Four electrodes331, 332. 333 and 334 are shown disposed around pulmonary vein 324 so asto surround it. With a potential difference applied across some of theelectrodes, simulation results can be obtained based on realistic valuesof electrical material properties for the various regions.

A simulation result in the form of a shaded contour plot of the electricpotential is shown in FIG. 22 for the case where a DC voltage is appliedacross a single anode electrode 332 and a single cathode electrode 334on opposite sides of the blood pool region 324, with a potentialdifference of 750 V applied across anode and cathode. FIG. 23 shows theelectric field intensity as a shaded contour plot where regions with anelectric field strength of magnitude at least 200 V/cm (generally neededto cause irreversible electroporation ablation of myocytes) areindicated in the shaded areas. It is apparent that these ablatedregions, indicated by region 341 around the anode electrode and region342 around the cathode electrode, cover a significant fraction of acontour around pulmonary vein 324.

Likewise, for the case when electrodes 331 and 332 are set to be anodeelectrodes and electrodes 333 and 334 are defined to be cathodeelectrodes, with a potential difference of about 750 V applied acrossanode and cathode, FIG. 24 shows the electric field intensity as ashaded contour plot where regions with an electric field strength ofmagnitude at least about 200 V/cm are indicated in the shaded areas. Itis apparent that in this case, the ablated region encompasses the entirecontour around the pulmonary vein 324. Thus, the catheter devices withflexible electrodes, according to some embodiments, can be effectivelyutilized for rapid ablation therapy by the application of irreversibleelectroporation voltages. As can be seen from FIG. 24, the areas whereelectric field intensities are sufficiently large to generateirreversible electroporation occur substantially in the region betweenthe electrodes, thus minimizing any potential damage to outer areas.Further, the applied voltage pulse level that is required to generateeffective ablation can be significantly reduced; in the above simulationa voltage of about 750 V is seen to be sufficient to generateirreversible electroporation everywhere in a region of interest. Thisfurther enhances the safety of the procedure by reducing the likelihoodof generating local electric fields that may be large enough to generatesparking or local dielectric breakdown as well as reduce the intensityof muscular contractions. The need for precise positioning of theelectrodes is also reduced, leading to an overall faster therapeuticprocedure.

FIG. 25 shows a portion of a user interface of the electroporationsystem for selection (with graphical buttons 117 and 118) of anode andcathode electrodes, with two catheters connected to the system. Theproximal leads of the two catheters (and thus the respective cathetersthemselves) are schematically indicated by 110 and 111, which each havefour flexible electrodes. For example, the catheter 111 has flexibleelectrodes labeled 361, 362, 371 and 372 in FIG. 25. Secondary catheter360 branches out from a proximal portion of catheter 111, whilesecondary catheter 366 branches out from a mid-portion of catheter 111.Secondary catheter 360 has flexible electrodes 363 and 364 respectively,while secondary catheter 366 has flexible electrodes 368 and 369respectively. Electrodes 361, 362, 363 and 364 thus encircle thepulmonary vein labeled 381, while electrodes 368, 369, 372 and 371encircle the pulmonary vein labeled 380.

The buttons 117 and 118 can enable the selection of appropriateelectrodes on the catheters as respectively anode or cathode with a“Continue” button 706. Once the selection is made, the appropriateelectrodes are colored differently to indicate anode or cathodeelectrodes as shown in FIG. 17, where electrodes 372 and 368 have beenmarked respectively as anode electrode and cathode electrode,respectively on primary catheter 111 and secondary catheter 366. Thisselection has been shown for purely illustrative purposes. Otherembodiments of user interface and mode of electrode selection can beimplemented by one skilled in the art based on the teachings herein.

While various specific examples and embodiments of systems and tools forselective tissue ablation with irreversible electroporation weredescribed in the foregoing for illustrative and exemplary purposes, itshould be clear that a wide variety of variations and additional oralternate embodiments could be conceived or constructed by those skilledin the art based on the teachings disclosed herein. While specificmethods of control and voltage application from a generator capable ofselective excitation of sets of electrodes were disclosed, personsskilled in the art would recognize that any of a wide variety of othercontrol or user input methods and methods of electrode subset selectionetc. can be implemented without departing from the scope of theembodiments disclosed herein. Further, while some embodiments thevoltage signals used in the ablation process are DC voltages or DCvoltage pulses, in other embodiments the voltage signals can be ACvoltages, or each voltage pulse can itself include time-varyingcomponents. Likewise, while the foregoing described a magnet-basedscheme for positioning and attachment of catheters to each other, itshould be apparent that other methods could be implemented for thispurpose, including mechanical means using small manipulator arms orcatches, pneumatically driven means, and so on, as can be conceived bythose skilled in the art by employing the principles and teachingsdisclosed herein without departing from the scope of the embodimentsdisclosed herein.

Some embodiments described herein relate to a computer storage productwith a non-transitory computer-readable medium (also referred to as anon-transitory processor-readable medium) having instructions orcomputer code thereon for performing various computer-implementedoperations. The computer-readable medium (or processor-readable medium)is non-transitory in the sense that it does not include transitorypropagating signals (e.g., a propagating electromagnetic wave carryinginformation on a transmission medium such as space or a cable). Themedia and computer code (also referred to herein as code) may be thosedesigned and constructed for the specific purpose or purposes. Examplesof non-transitory computer-readable media include, but are not limitedto: flash memory, magnetic storage media such as hard disks, opticalstorage media such as Compact Disc/Digital Video Discs (CD/DVDs),Compact Disc-Read Only Memories (CD-ROMs), magneto-optical storage mediasuch as optical disks, carrier wave signal processing modules, andhardware devices that are specially configured to store and executeprogram code, such as Application-Specific Integrated Circuits (ASICs),Programmable Logic Devices (PLDs), Read-Only Memory (ROM) andRandom-Access Memory (RAM) devices.

Examples of computer code include, but are not limited to, micro-code ormicro-instructions, machine instructions, such as produced by acompiler, code used to produce a web service, and files containinghigher-level instructions that are executed by a computer using aninterpreter. For example, embodiments may be implemented using Java,C++, or other programming languages and/or other development tools.

1: An apparatus, comprising: a shaft including a plurality of steppedsections along the length of the shaft; and a plurality of electrodesdisposed along the length of the shaft, each electrode characterized bya geometric aspect ratio of the length of the electrode to the outerdiameter of the electrode, each electrode located at a different steppedsection of the plurality of stepped sections of the shaft, eachelectrode including a set of leads, each lead of the set of leadsconfigured to attain an electrical voltage potential of at least about 1kV, wherein the geometric aspect ratio of at least one electrode of theplurality of electrodes is in the range between about 3 and about
 20. 2:The apparatus of claim 1, wherein at least one electrode of theplurality of electrodes includes a coiled length of an electricalconductor. 3: The apparatus of claim 1, the shaft further including alumen formed therein, the apparatus configured for, when a guidewire isdisposed in the lumen during use, movement along the guidewire. 4-9.(canceled) 10: A device, comprising: a primary catheter, including: oneor more electrodes disposed in an intermediate portion of the primarycatheter; one or more electrodes disposed in a distal portion of theprimary catheter; two or more channels configured for passage ofsecondary catheters, each channel continuous from a proximal portion ofthe primary catheter to a lateral exit position on the primary catheter,one or more magnetic members disposed in the intermediate portion of theprimary catheter; and a magnetic member disposed in the distal portionof the primary catheter; at least two secondary catheters configured forpassage through the primary catheter device, each secondary catheterincluding: one or more electrodes in its respective distal portion; anda magnetic member in its respective distal portion; for each electrodeof the primary catheter and each electrode of the secondary catheter, anelectrical lead attached to the corresponding electrode, each leadconfigured for, during use, being at an electrical voltage potential ofat least 1 kV without resulting in dielectric breakdown of the two ormore channels of the primary catheter, wherein a geometric aspect ratioof at least one of the electrodes of the primary catheter device is inthe range between about 3 and about
 20. 11: The device of claim 10,wherein a geometric aspect ratio of at least one electrode of one of thesecondary catheter devices is in the range between about 3 and about 20.12: The device of claim 10, wherein the magnetic member disposed in thedistal portion of the primary catheter includes one magnetic poleoriented substantially longitudinally and one magnetic pole orientedsubstantially laterally with respect to the elongate axis of the primarycatheter. 13: The device of claim 10, wherein the at least one magneticmember disposed in the intermediate portion of the primary catheterdevice includes an electromagnet. 14: The device of claim 10, furthercomprising a lumen configured for, during use, introducing the deviceover a guidewire. 15: The device of claim 10, wherein the magneticmember in at least one secondary catheter device includes magnetizablematerial. 16-21. (canceled) 22: An apparatus, comprising: a cathetershaft; a set of flexible electrodes disposed along the length of thecatheter shaft, each flexible electrode characterized by a geometricaspect ratio of the length of the flexible electrode to the outerdiameter of the flexible electrode, each flexible electrode including aset of conducting rings separated by spaces and disposed along thecatheter shaft, the set of conducting rings of each flexible electrodeelectrically connected together so as to electrically define a commonelectrical potential for the each electrode, the catheter shaftincluding gaps configured for separating adjacent flexible electrodes ofthe set of flexible electrodes; and electrical leads attached to each ofthe flexible electrodes, each electrical lead configured for attainingan electrical voltage potential of at least 1 kV, wherein the geometricaspect ratio of at least one of the flexible electrodes is in the rangebetween about 3 and about
 20. 23: The apparatus of claim 1, the shaftfurther including one or more magnetic members disposed in anintermediate portion of the shaft. 24: The apparatus of claim 23,wherein at least one of the magnetic members disposed in theintermediate portion of the shaft includes an electromagnet. 25: Theapparatus of claim 1, the shaft further including a magnetic memberdisposed in a distal portion of the shaft. 26: The apparatus of claim25, wherein the magnetic member disposed in the distal portion of theshaft includes one magnetic pole oriented substantially longitudinallyand one magnetic pole oriented substantially laterally with respect tothe elongate axis of the shaft. 27: The apparatus of claim 1, the shaftfurther including two or more channels, each channel continuous from aproximal portion of the shaft to a lateral exit position on the shaft.28: The apparatus of claim 27, wherein the two or more channels areconfigured for passage of secondary catheters. 29: The apparatus ofclaim 22, wherein a width of each of the conducting rings is in therange between about 0.5 mm and about 6 mm. 30: The apparatus of claim29, wherein the width of adjacent conducting rings is different withineach of the flexible electrodes. 31: The apparatus of claim 22, whereinthe space between adjacent conducting rings is in the range betweenabout 1 mm and about 4 mm. 32: The apparatus of claim 22, wherein thegaps may be in the range between about 2 mm and about 12 mm.